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G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 15231

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Prof. Dr. J. Adolfo García-Sáinz

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Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ap. Postal 70-248, Ciudad de México CP 04510, Mexico
Interests: GPCR signaling; receptor phosphorylation; adrenergic receptors; signal transduction; phosphorylation; protein kinase C; adrenergic agents

Special Issue Information

Dear Colleagues,

G-protein-coupled receptors (GPCRs) are sensors of the external (light, odors, and tastants) and internal (hormones, neurotransmitters, and local hormones) milieux, mediating physiological functions and participating in the pathophysiology of many diseases. Therefore, GPCRs are targets of a large percentage of prescribed and illegal drugs. Pharmacology and therapeutics are advancing, leading to the discovery of full, partial, inverse, and biased agonists, antagonists, allosteric modulators, inducers of internalization and degradation, and the identification of unexpected actions of substances already employed in current medical practice, all of which has led to the development of targeted therapies for different maladies. Similarly, molecular strategies have allowed, at least partially, for the elucidation of how GPCR structure is modulated by different ligands and by proteins that regulate them through interaction and post-translational modifications, thus evidencing the formation of receptor complexes and their roles in signaling at the plasma membrane and endosomes. The current Special Issue welcomes submissions on these areas.

Prof. Dr. J. Adolfo García-Sáinz
Guest Editor

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Keywords

GPCR
cell signaling
small molecule drugs
biased signaling
endosomal signaling
post-translational modification
GPCR internalization
phosphorylation barcode

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Published Papers (9 papers)

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Research

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18 pages, 3870 KiB

Open AccessArticle

A Machine Learning Algorithm Suggests Repurposing Opportunities for Targeting Selected GPCRs

by Shayma El-Atawneh and Amiram Goldblum

Int. J. Mol. Sci. 2024, 25(18), 10230; https://doi.org/10.3390/ijms251810230 - 23 Sep 2024

Viewed by 976

Abstract

Repurposing utilizes existing drugs with known safety profiles and discovers new uses by combining experimental and computational approaches. The integration of computational methods has greatly advanced drug repurposing, offering a rational approach and reducing the risk of failure in these efforts. Recognizing the potential for drug repurposing, we employed our Iterative Stochastic Elimination (ISE) algorithm to screen known drugs from the DrugBank database. Repurposing in our hands is based on computer models of the actions of ligands: the ISE algorithm is a machine learning tool that creates ligand-based models by distinguishing between the physicochemical properties of known drugs and those of decoys. The models are large sets of “filters” made out, each, of molecular properties. We screen and score external sets of molecules (in our case- the DrugBank molecules) by our agonism and antagonism models based on published data (i.e., IC₅₀, K_i, or EC₅₀) and pick the top-scoring molecules as candidates for experiments. Such agonist and antagonist models for six G-protein coupled receptors (GPCRs) families facilitated the identification of repurposing opportunities. Our screening revealed 5982 new potential molecular actions (agonists, antagonists), which suggest repurposing candidates for the cannabinoid 2 (CB2), histamine (H1, H3, and H4), and dopamine 3 (D3) receptors, which may be useful to treat conditions such as neuroinflammation, obesity, allergic dermatitis, and drug abuse. These sets of best candidates should now be examined by experimentalists: based on previous such experiments, there is a very high chance of discovering novel highly bioactive molecules. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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13 pages, 1883 KiB

Open AccessArticle

C-C Chemokine Receptor 7 Promotes T-Cell Acute Lymphoblastic Leukemia Invasion of the Central Nervous System via β2-Integrins

by Cesar I. Cardona, Alondra Rodriguez, Vivian C. Torres, Anahi Sanchez, Angel Torres, Aaron E. Vazquez, Amy E. Wagler, Michael A. Brissette, Colin A. Bill and Charlotte M. Vines

Int. J. Mol. Sci. 2024, 25(17), 9649; https://doi.org/10.3390/ijms25179649 - 6 Sep 2024

Viewed by 775

Abstract

C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL19_8-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca²⁺ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ β2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL19_8-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent β2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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11 pages, 1967 KiB

Open AccessArticle

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α₂-Adrenergic Receptors in PC12 Cells

by Deepika Nagliya, Teresa Baggio Lopez, Giselle Del Calvo, Renee A. Stoicovy, Jordana I. Borges, Malka S. Suster and Anastasios Lymperopoulos

Int. J. Mol. Sci. 2024, 25(10), 5227; https://doi.org/10.3390/ijms25105227 - 11 May 2024

Viewed by 1415

Abstract

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α₂-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α₂-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca²⁺ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α_2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α_2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α_2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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18 pages, 3110 KiB

Open AccessArticle

Real-Time Determination of Intracellular cAMP Reveals Functional Coupling of G_s Protein to the Melatonin MT₁ Receptor

by Lap Hang Tse, Suet Ting Cheung, Seayoung Lee and Yung Hou Wong

Int. J. Mol. Sci. 2024, 25(5), 2919; https://doi.org/10.3390/ijms25052919 - 2 Mar 2024

Viewed by 1535

Abstract

Melatonin is a neuroendocrine hormone that regulates the circadian rhythm and many other physiological processes. Its functions are primarily exerted through two subtypes of human melatonin receptors, termed melatonin type-1 (MT₁) and type-2 (MT₂) receptors. Both MT₁ and MT₂ receptors are generally classified as G_i-coupled receptors owing to their well-recognized ability to inhibit cAMP accumulation in cells. However, it remains an enigma as to why melatonin stimulates cAMP production in a number of cell types that express the MT₁ receptor. To address if MT₁ can dually couple to G_s and G_i proteins, we employed a highly sensitive luminescent biosensor (GloSensor^TM) to monitor the real-time changes in the intracellular cAMP level in intact live HEK293 cells that express MT₁ and/or MT₂. Our results demonstrate that the activation of MT₁, but not MT₂, leads to a robust enhancement on the forskolin-stimulated cAMP formation. In contrast, the activation of either MT₁ or MT₂ inhibited cAMP synthesis driven by the activation of the G_s-coupled β₂-adrenergic receptor, which is consistent with a typical G_i-mediated response. The co-expression of MT₁ with G_s enabled melatonin itself to stimulate cAMP production, indicating a productive coupling between MT₁ and G_s. The possible existence of a MT₁-G_s complex was supported through molecular modeling as the predicted complex exhibited structural and thermodynamic characteristics that are comparable to that of MT₁-G_i. Taken together, our data reveal that MT₁, but not MT₂, can dually couple to G_s and G_i proteins, thereby enabling the bi-directional regulation of adenylyl cyclase to differentially modulate cAMP levels in cells that express different complements of MT₁, MT₂, and G proteins. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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18 pages, 9636 KiB

Open AccessArticle

Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells

by Frida L. Martínez-Cuevas, Silvia L. Cruz and Claudia González-Espinosa

Int. J. Mol. Sci. 2024, 25(4), 2137; https://doi.org/10.3390/ijms25042137 - 10 Feb 2024

Viewed by 1762

Abstract

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates μ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express μ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca²⁺]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca²⁺]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of μ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between μ-opioid and TLR4 receptors. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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13 pages, 2215 KiB

Open AccessArticle

Control of CCR5 Cell-Surface Targeting by the PRAF2 Gatekeeper

by Elisa Da Silva, Mark G. H. Scott, Hervé Enslen and Stefano Marullo

Int. J. Mol. Sci. 2023, 24(24), 17438; https://doi.org/10.3390/ijms242417438 - 13 Dec 2023

Viewed by 1433

Abstract

The cell-surface targeting of neo-synthesized G protein-coupled receptors (GPCRs) involves the recruitment of receptors into COPII vesicles budding at endoplasmic reticulum exit sites (ERESs). This process is regulated for some GPCRs by escort proteins, which facilitate their export, or by gatekeepers that retain the receptors in the ER. PRAF2, an ER-resident four trans- membrane domain protein with cytoplasmic extremities, operates as a gatekeeper for the GB1 protomer of the heterodimeric GABA_B receptor, interacting with a tandem di-leucine/RXR retention motif in the carboxyterminal tail of GB1. PRAF2 was also reported to interact in a two-hybrid screen with a peptide corresponding to the carboxyterminal tail of the chemokine receptor CCR5 despite the absence of RXR motifs in its sequence. Using a bioluminescence resonance energy transfer (BRET)-based subcellular localization system, we found that PRAF2 inhibits, in a concentration-dependent manner, the plasma membrane export of CCR5. BRET-based proximity assays and Co-IP experiments demonstrated that PRAF2/CCR5 interaction does not require the presence of a receptor carboxyterminal tail and involves instead the transmembrane domains of both proteins. The mutation of the potential di-leucine/RXR motif contained in the third intracellular loop of CCR5 does not affect PRAF2-mediated retention. It instead impairs the cell-surface export of CCR5 by inhibiting CCR5’s interaction with its private escort protein, CD4. PRAF2 and CD4 thus display opposite roles on the cell-surface export of CCR5, with PRAF2 inhibiting and CD4 promoting this process, likely operating at the level of CCR5 recruitment into COPII vesicles, which leave the ER. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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15 pages, 3642 KiB

Open AccessArticle

Roles of the α_1B-Adrenergic Receptor Phosphorylation Domains in Signaling and Internalization

by David A. Hernández-Espinosa, Rocío Alcántara-Hernández, K. Helivier Solís and J. Adolfo García-Sáinz

Int. J. Mol. Sci. 2023, 24(23), 16963; https://doi.org/10.3390/ijms242316963 - 30 Nov 2023

Cited by 1 | Viewed by 1013

Abstract

The function of the α_1B-adrenergic receptor phosphorylation sites previously detected by mass spectrometry was evaluated by employing mutants, substituting them with non-phosphorylatable amino acids. Substitution of the intracellular loop 3 (IL3) sites did not alter baseline or stimulated receptor phosphorylation, whereas substitution of phosphorylation sites in the carboxyl terminus (Ctail) or both domains (IL3/Ctail) markedly decreased receptor phosphorylation. Cells expressing the IL3 or Ctail receptor mutants exhibited a noradrenaline-induced calcium-maximal response similar to those expressing the wild-type receptor, and a shift to the left in the concentration–response curve to noradrenaline was also noticed. Cells expressing the IL3/Ctail mutant exhibited higher apparent potency and increased maximal response to noradrenaline than those expressing the wild-type receptor. Phorbol ester-induced desensitization of the calcium response to noradrenaline was reduced in cells expressing the IL3 mutant and abolished in cells in which the Ctail or the IL3/Ctail were modified. In contrast, desensitization in response to preincubation with noradrenaline was unaffected in cells expressing the distinct receptor mutants. Noradrenaline-induced ERK phosphorylation was surprisingly increased in cells expressing IL3-modified receptors but not in those expressing receptors with the Ctail or IL3/Ctail substitutions. Our data indicate that phosphorylation sites in the IL3 and Ctail domains mediate and regulate α_1B-adrenergic receptor function. Phorbol ester-induced desensitization seems to be closely associated with receptor phosphorylation, whereas noradrenaline-induced desensitization likely involves other elements. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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17 pages, 4596 KiB

Open AccessArticle

Oncogenic Gαq activates RhoJ through PDZ-RhoGEF

by Rodolfo Daniel Cervantes-Villagrana, Víctor Manuel Color-Aparicio, Alejandro Castillo-Kauil, Irving García-Jiménez, Yarely Mabell Beltrán-Navarro, Guadalupe Reyes-Cruz and José Vázquez-Prado

Int. J. Mol. Sci. 2023, 24(21), 15734; https://doi.org/10.3390/ijms242115734 - 29 Oct 2023

Cited by 1 | Viewed by 2807

Abstract

Oncogenic Gα_q causes uveal melanoma via non-canonical signaling pathways. This constitutively active mutant GTPase is also found in cutaneous melanoma, lung adenocarcinoma, and seminoma, as well as in benign vascular tumors, such as congenital hemangiomas. We recently described that PDZ-RhoGEF (also known as ARHGEF11), a canonical Gα_12/13 effector, is enabled by Gα_s Q227L to activate CdcIn addition, and we demonstrated that constitutively active Gα_q interacts with the PDZ-RhoGEF DH-PH catalytic module, but does not affect its binding to RhoA or Cdc. This suggests that it guides this RhoGEF to gain affinity for other GTPases. Since RhoJ, a small GTPase of the Cdc42 subfamily, has been involved in tumor-induced angiogenesis and the metastatic dissemination of cancer cells, we hypothesized that it might be a target of oncogenic Gα_q signaling via PDZ-RhoGEF. Consistent with this possibility, we found that Gα_q Q209L drives full-length PDZ-RhoGEF and a DH-PH construct to interact with nucleotide-free RhoJ-G33A, a mutant with affinity for active RhoJ-GEFs. Gα_q Q209L binding to PDZ-RhoGEF was mapped to the PH domain, which, as an isolated construct, attenuated the interaction of this mutant GTPase with PDZ-RhoGEF’s catalytic module (DH-PH domains). Expression of these catalytic domains caused contraction of endothelial cells and generated fine cell sprouts that were inhibited by co-expression of dominant negative RhoJ. Using relational data mining of uveal melanoma patient TCGA datasets, we got an insight into the signaling landscape that accompanies the Gα_q/PDZ-RhoGEF/RhoJ axis. We identified three transcriptional signatures statistically linked with shorter patient survival, including GPCRs and signaling effectors that are recognized as vulnerabilities in cancer cell synthetic lethality datasets. In conclusion, we demonstrated that an oncogenic Gα_q mutant enables the PDZ-RhoGEF DH-PH module to recognize RhoJ, suggesting an allosteric mechanism by which this constitutively active GTPase stimulates RhoJ via PDZ-RhoGEF. These findings highlight PDZ-RhoGEF and RhoJ as potential targets in tumors driven by mutant Gαq. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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Review

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20 pages, 1020 KiB

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Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature

by Akram M. Eraky, Yashwanth Yerramalla, Adnan Khan, Yasser Mokhtar, Mostafa Alamrosy, Amr Farag, Alisha Wright, Matthew Grounds and Nicole M. Gregorich

Int. J. Mol. Sci. 2024, 25(15), 8058; https://doi.org/10.3390/ijms25158058 - 24 Jul 2024

Viewed by 2239

Abstract

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling, Regulation and Therapeutic Opportunities)

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